In contrast to the non-uremic population, high body mass index (BMI) has been shown to be associated with better survival in dialysis patients and hence fat is considered to be beneficial in dialysis patients. This raises the question if uremia modifies the molecular signaling pathways that mediate the effects of adipocytes on insulin resistance, dyslipidemia, hypertension, inflammation and atherosclerosis in the non-uremic population. If not, what are the clinical effects of these molecular signals and what therapeutic interventions could modulate these signals in dialysis patients? Adipokines, such as tumor necrosis factor-1 (TNF-1), interleukin-6 (IL-6), plasminogen activator inhibitor-1 (PAI-1), leptin and adiponectin, are hormones secreted by adipocytes that mediate the effects of adiposity on clinical outcomes. Whether the adipokines bear similar relationships with adiposity and clinical effects in uremia is unclear at present. We hypothesize that (1) Uremia does not reverse the adipocyte production of adipokines or the metabolic effects of adipokines on inflammation, oxidative stress and insulin resistance. Hence, the direction of the associations of adiposity with adipokines and the associations of adipokines with inflammation, oxidative stress and insulin resistance in hemodialysis patients are the same as described in the non-uremic population;and (2) intervention with pioglitazone, a peroxisome proliferator- activated receptor (PPAR)-3 ligand, will up-regulate the anti-inflammatory adipokine adiponectin and down- regulate the pro-inflammatory adipokines, TNF-1 and IL-6. Hence, pioglitazone should decrease inflammation, oxidative stress and preserve muscle mass in overweight or obese diabetic or non-diabetic chronic dialysis patients. This revised application seeks to (1) further understand the biology and pathophysiology of adiposity and adipocytes in uremia by performing an observational study;and (2) test the causal relationships between adipose tissue adipokine expression and plasma adipokine concentrations with their clinical metabolic effects in uremia by an interventional study. 1. Observational component: This will examine in 120 prevalent chronic hemodialysis patients (50 will undergo subcutaneous fat biopsy) with a wide range of body mass index (BMI): i. the associations of visceral fat mass, as assessed by magnetic resonance imaging (MRI), with a. adipokine (adiponectin, TNF-1 and IL-6) expression in biopsied subcutaneous fat tissues b. plasma levels of adipokines (adiponectin, TNF-1, IL-6, PAI-1 and leptin) and c. clinical metabolic parameters (inflammation as indicated by plasma hsCRP levels, oxidative stress as indicated by plasma F2-isoprostanes and insulin resistance as indicated by Homeostatic Model of Assessment). ii. the associations of subcutaneous fat adipokine expression with plasma adipokine levels and the above clinical metabolic parameters. 2. Interventional component: This is a randomized placebo-controlled trial of the PPAR3 ligand pioglitazone in 100 overweight or obese prevalent hemodialysis patients. These patients will be randomized and followed for 24 weeks. The endpoints will be subcutaneous adipose tissue adipokine expression, plasma adipokine concentrations, plasma markers of inflammation, oxidative stress and insulin resistance as well as mid-thigh muscle mass quantified by MRI. These studies will enhance our understanding of the biology and pathobiology of adipocytes as well as the apparent paradox between adiposity and clinical outcomes in uremia. A positive result of our randomized trial will also pave the way for a large, definitive interventional trial of PPAR3 ligand drugs to improve the clinical outcomes of dialysis patients. The revised application has addressed all the comments of the Reviewers. In particular, we have simplified the application, deleted the HEMO Study component, and extensively revised the methods section to clarify the study design and organization. PUBLIC HEALTH RELEVANCE: If fat cells produce harmful proteins, therapy targeted towards decreasing the production of these proteins will ultimately decrease the morbidity and mortality in obese dialysis patients.